Cigarette smoking contributes to approximately 480,000 deaths in the United States annually. Despite the known health risks associated with smoking, approximately 11.5% of American adults were identified as current smokers in 2021, with large differences in smoking rates found based on a variety of demographic factors. For example, smoking rates were higher among men than women (13.1% vs. 10.1%), highest among adults between the ages of 45 and 64 (14.9%), highest among low-income adults (18.3%), and lowest among those with a graduate degree (3.2%). Geographically, within the United States, smoking rates were higher in the Midwest (14%) and South (12.4%) than in the West (8.9%) or Northeast (10.4%) [3].

Cigarette smoking contributes to approximately 480,000 deaths in the United States annually. Despite the known health risks associated with smoking, approximately 11.5% of American adults were identified as current smokers in 2021, with large differences in smoking rates found based on a variety of demographic factors. For example, smoking rates were higher among men than women (13.1% vs. 10.1%), highest among adults between the ages of 45 and 64 (14.9%), highest among low-income adults (18.3%), and lowest among those with a graduate degree (3.2%). Geographically, within the United States, smoking rates were higher in the Midwest (14%) and South (12.4%) than in the West (8.9%) or Northeast (10.4%) [3].

Although the prevalence of smoking continues to be high, the proportion of adults in the United States who smoke has decreased substantially since the 1965 when smoking prevalence among adults was more than 50%. However, the decrease has not been observed consistently among the population, with smoking rates in some subpopulations remaining quite high. Although smoking cessation is difficult, more than 60% of people who have ever smoked have successfully quit [2]. The vast majority of all smokers report first use in adolescence or young adulthood, with 87% of current smokers reporting their first use before the age of 18 and 95% before the age of 21 [4]. These data suggest the importance of preventing tobacco initiation among youth and emphasize the need for public health policies that achieve this goal.

The focus of this continuing education course is on cigarette smoking; however, it is important to be aware of both the wide variety of tobacco products currently available and of the rapid changes that are occurring in the patterns of tobacco product use. In addition to combustible cigarettes, multiple other tobacco products, including electronic nicotine delivery systems (commonly known as e-cigarettes), cigars, smokeless tobacco products, hookah, and pipe tobacco, are being used. In particular, it is important to be aware of the increasing prevalence of e-cigarette use especially among adolescents and young adults. Data from 2023 found that among adolescents, e-cigarette use has surpassed the use of combustible cigarettes, with 7.7% of middle and high school students reporting use of e-cigarettes within the past 30 days compared to 1.6% reporting use of cigarettes [1]. In addition, youth who utilize e-cigarettes are more likely to start smoking combustible cigarettes [8].

In the United States, tobacco use results in approximately 660,000 new cancer cases and 343,000 cancer deaths annually. The number of cancer diagnoses attributable to tobacco use represents approximately 40% of all cancer deaths in the United States [11]. Smoking results in an approximately 25-fold increase in lung cancer risk and it has been estimated that 90% of all lung cancers are attributable to smoking. Although smoking is most closely associated with increased lung cancer incidence, it is also a risk factor for numerous other cancers, including cancers of the esophagus, larynx, stomach, liver, pancreas, bladder, kidney, and colon [12].

The health benefits of smoking cessation are considerable, with both short-term and long-term health effects observed after cessation. Within 24 hours of quitting, nicotine levels in the blood drop to zero. Several days after quitting, carbon monoxide levels drop to the same level as nonsmokers. Within a year of quitting, coughing and shortness of breath decrease. The risk of heart attack drops sharply after 1 to 2 years have passed since quitting. After 3 to 6 years, the risk of coronary heart disease is approximately half that of a continuing smoker. Within 5 to 10 years of quitting smoking, risk for stroke decreases to approximately that of a nonsmoker, as does the risk of cancers of the mouth, throat, and voice box. Within 10 years of quitting, the added risk of lung cancer drops by half, and the risk of bladder, esophagus, and kidney cancers decreases. Approximately 15 years after quitting, the risk of coronary heart disease drops to approximately that of a nonsmoker [14].

Despite its role as the primary addictive compound in tobacco, nicotine is a relatively small contributor to the overall health risks associated with smoking. It is rather many of the other constituents in tobacco smoke that are responsible for the negative health effects. Tobacco smoke contains thousands of chemicals that are deposited in the large and small airways when inhaled. Although the relative contribution of each individual compound to the development and progression of disease is not clear, some compounds' role in contributing to disease has been better studied. The presence of oxidant chemicals and particulates is thought to lead to inflammation whereas the presence of carbon monoxide leads to reduced oxygen availability—both of these then lead to increased cardiovascular morbidity and mortality. The presence of tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, and other carcinogens likely contributes to the development of cancer [2].

Approximately 70% of smokers report that they would like to quit smoking and over 50% of adult daily smokers try to quit each year. An increasing number of people are quitting smoking successfully; in 2020, 8.5% of smokers successfully quit in the past year, compared to 7.5% in 2019 [19]. In clinical studies in which smokers receive both behavioral and pharmacological interventions, quit rates are substantially higher, but unfortunately even in these circumstances fewer than 30% of those who try to quit smoking are able to achieve long-term abstinence [18]. There is therefore clearly a need for knowledgeable healthcare professionals who can suggest appropriate pharmacotherapy for patients and instruct them on how to properly use it so as to maximize smoking cessation success rates.

Patients unwilling to quit may respond to brief interventions that are based on principles of motivational interviewing. Motivational interviewing is a directive, patient-centered counseling intervention with the goal of eliciting behavioral change by helping to explore and resolve ambivalence. This approach is intended to increase the likelihood that a smoking cessation attempt will be made. Its four general principles are express empathy, develop discrepancy, roll with resistance, and support self-efficacy [18]. Table 1, taken from the practice guidelines, details approaches and statements that can be used when counseling a smoker [18].

All of the available dosage forms of NRT work in part by alleviating or minimizing nicotine withdrawal symptoms that typically occur after cessation of tobacco. Withdrawal symptoms generally peak within one to two weeks after quitting but may persist for months. The time course of these symptoms may help explain why most lapses occur within the first week of cessation (and many within the first 24 hours). Nicotine withdrawal symptoms include irritability, anxiety, difficulty concentrating, increased appetite, restlessness, depressed mood, and insomnia. Use of nicotine replacement therapy decreases the intensity of these symptoms relative to use of placebo or no treatment. In addition to decreasing withdrawal symptoms, nicotine from NRT might provide some of the perceived benefits that smokers experience from cigarettes. For example, smokers often report that smoking decreases stress or anxiety (although smoking may in fact be relieving withdrawal symptoms). To the extent that these perceived benefits are due to nicotine, replacing the nicotine from cigarettes with another source may result in similar effects and thereby reduce the likelihood of smoking lapses [18,22].

The nicotine gum is available in two strengths (2 mg, 4 mg), in multiple flavors (such as original, mint, and cinnamon, among others), and in both brand-name and generic form. Dosing for the nicotine gum is based on the time to first cigarette, which is a surrogate measure for the degree of nicotine dependence. If the first cigarette of the day is smoked within 30 minutes of waking, the 4-mg dose should be used. Otherwise, the 2-mg dose should be used. Nicotine concentrations peak approximately 30 minutes after nicotine gum use is started. This relative rapid increase means that unlike the nicotine patch (described subsequently), the nicotine gum can be used to decrease craving and withdrawal symptom severity when smokers find that they are experiencing an urge to smoke, although for many smokers craving relief may not occur quickly enough to avoid a lapse.

The nicotine patch is different from all of the other dosage forms of NRT in that it delivers a constant amount of nicotine over a prolonged period of time. Nicotine concentrations following the application of the nicotine patch increase gradually over several hours and then remain relatively steady for the duration that it is worn. An advantage of this pharmacokinetic profile is that smokers need only to remember to place the patch once per day. A disadvantage is that the patch cannot be used for acute relief of craving and withdrawal symptoms.

As is the case with the nicotine gum and lozenge, the patch is available over the counter in both brand and generic forms. The patch comes in three dosages (21-mg, 14-mg, and 7-mg). The initial dose, per the labeling, is based on the number of cigarettes that are smoked per day. Those that smoke fewer than 10 cigarettes per day start with the 14-mg patch, whereas those smoking more than 10 cigarettes per day start with the 21-mg patch. The labeled dosage of the patch is the amount of nicotine delivered over a 24-hour period. The nicotine patch is designed to be worn for 24 hours; smokers who have sleep disturbances while wearing the patch overnight may benefit from removing the patch at bedtime.

Absorption of nicotine after using the nasal spray is via the nasal mucosa and is substantially more rapid than other dosage forms of NRT, with peak concentrations occurring within approximately 10 to 15 minutes after use. Although faster than other dosage forms of NRT, this is still significantly slower than occurs after cigarette smoking. An advantage of the more rapid nicotine absorption is that withdrawal symptom relief should occur more quickly than with other NRT dosage forms. Nonetheless, usage of this product is limited due to a high rate of adverse events.

Smokers should begin taking bupropion one to two weeks prior to their quit date to allow steady-state concentrations to be achieved. Because a dose-related incidence of seizures has been reported, bupropion is contraindicated in those with a seizure disorder or who are at increased risk for seizures, for example, those with a current or prior diagnosis of eating disorders or after acute discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Consistent with the labeling of all antidepressants, bupropion carries a black box warning regarding an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults.

When used as an aid to smoking cessation treatment, the sustained release dosage form of bupropion is initiated at 150 mg daily for the first three days, then increased to 150 mg twice daily separated by at least 8 hours. Treatment should continue for at least 7 to 12 weeks and can be extended for up to 6 months if appropriate. The most common side effects of bupropion include insomnia and dry mouth, with other side effects such as headache, agitation, dizziness, nausea, and constipation also reported. To prevent insomnia, it is sometimes recommended that the evening dose of bupropion is given several hours before bedtime (but at least 8 hours after the first dose of the day). In some patients, bupropion can cause increases in blood pressure. Although in most cases these increases are relatively small, blood pressure should be monitored, particularly in those who use bupropion with the nicotine patch as the increases may be larger in these patients. Bupropion is metabolized by CYP2B6, and therefore bupropion concentration may be affected by drugs that alter the activity of this isoenzyme. Bupropion is also known to be an inhibitor of the CYP2D6 isoenzyme, which is responsible for the metabolism of many medications. When both starting and discontinuing bupropion, it is therefore necessary to determine if the patient is taking any medications metabolized via this route to determine if increased monitoring or dose adjustments may be needed [18,22].

Varenicline is a partial agonist at the α4β2 nicotinic acetylcholine receptor, which is thought to be the major receptor involved in nicotine addiction. As a partial agonist, varenicline could relieve the symptoms of nicotine withdrawal while also blocking the effects of nicotine from any cigarettes that are smoked. This would thereby decrease the chance that a smoking lapse would lead to a relapse. The efficacy of varenicline has been confirmed in multiple studies, with an analysis of 27 trials finding that the relative risk for abstinence at 6 months or longer for varenicline-treated smokers relative to those receiving placebo is 2.24 (95% CI 2.06 to 2.43). This effect is larger than those previously described for either bupropion or NRT, and indeed a meta-analysis has found that varenicline is more effective than either bupropion (relative risk of 1.39; 95% CI 1.25 to 1.54) or NRT (relative risk of 1.25; 95% CI 1.14 to 1.37) at increasing cessation rates [27].

Despite the documented efficacy of the first-line pharmacotherapies described previously, smoking cessation rates when using any of them remain relatively low, leading researchers and clinicians to examine if quit rates can be increased by combining several of the medications. Perhaps the most commonly used combination is the nicotine patch used on a scheduled basis combined with one of the other dosage forms (i.e., gum, lozenge, inhaler, nasal spray) of nicotine replacement therapy used on an as-needed basis. This combination allows for a basal level of nicotine to be obtained from the patch with additional nicotine provided by short-acting NRT formulations when smokers experience withdrawal symptoms or for situational urges for tobacco. A meta-analysis evaluating the data regarding this combination has confirmed its increased efficacy relative to use of a single NRT. Based on the results of nine trials, it was found that treatment with two types of NRT was more effective than the use of a single NRT product (relative risk = 1.34, 95% CI 1.18 to 1.51), with the resultant efficacy rates similar to treatment with varenicline. This approach is therefore recommended as a first-line treatment approach in some guidelines [18,24].

In addition to drug/drug interaction that can occur (e.g., due to bupropion's inhibitory effect on CYP2D6), it is important to be aware of how smoking, and therefore quitting, can impact medications that a smoker may be taking. Interactions between smoking and medications may be either pharmacokinetic (i.e., smoking impacts concentrations of the impacted drug) or pharmacodynamic (i.e., smoking impacts the effect of the impacted drug). A mechanism by which smoking can impact the concentrations of concurrently used medications is via the induction of the cytochrome P450 1A2 isoenzyme (CYP1A2). Polycyclic aromatic hydrocarbons in cigarette smoke increase the activity of this isoenzyme, which therefore results in lower concentrations of medications metabolized via this route [30]. Conversely, smoking cessation results in the reversal of this induction and can therefore lead to increases in the concentrations of medications metabolized via this route. A number of medications, such as clozapine and olanzapine among others, are known to be metabolized via CYP1A2.

One compound that is metabolized by CYP1A2 and commonly used by smokers is caffeine. Accordingly, the concentration of caffeine (after controlling for caffeine intake) is substantially higher in nonsmokers than in smokers. Upon cessation, the clearance of caffeine decreases, which leads to increased concentrations of caffeine if the amount of caffeine intake is not adjusted. Although it is not clear how higher caffeine concentrations impact cessation success, it is possible that the effects of increased caffeine concentrations (e.g., insomnia and irritability) may be interpreted by some smokers as withdrawal symptoms and thereby lead to smoking lapses. It is also possible that these symptoms of caffeine withdrawal are interpreted by smokers to be side effects of the medications that they are taking to help with the smoking cessation attempt. If this is the case, smokers may decrease the dose of these medications or discontinue taking them, thereby decreasing the probability of successful cessation. Smokers therefore should be informed that after quitting, they may experience greater caffeine effects despite there being no changes in their caffeine intake [32].